Effects of omecamtiv mecarbil on the contractile properties of skinned porcine left atrial and ventricular muscles

Tomohiro Nakanishi; Kotaro Oyama; Hiroyuki Tanaka; Fuyu Kobirumaki-Shimozawa; Shuya Ishii; Takako Terui; Shin'ichi Ishiwata; Norio Fukuda

doi:10.3389/fphys.2022.947206

Effects of omecamtiv mecarbil on the contractile properties of skinned porcine left atrial and ventricular muscles

Front Physiol. 2022 Aug 23:13:947206. doi: 10.3389/fphys.2022.947206. eCollection 2022.

Authors

Tomohiro Nakanishi^{1

2}, Kotaro Oyama^{1

3}, Hiroyuki Tanaka⁴, Fuyu Kobirumaki-Shimozawa¹, Shuya Ishii³, Takako Terui², Shin'ichi Ishiwata⁵, Norio Fukuda¹

Affiliations

¹ Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
² Department of Anesthesiology, The Jikei University School of Medicine, Tokyo, Japan.
³ Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology, Gunma, Japan.
⁴ Laboratory of Marine Biotechnology and Microbiology, Hokkaido University, Hakodate, Japan.
⁵ Department of Physics, Faculty of Science and Engineering, Waseda University, Tokyo, Japan.

Abstract

Omecamtiv mecarbil (OM) is a novel inotropic agent for heart failure with systolic dysfunction. OM prolongs the actomyosin attachment duration, which enhances thin filament cooperative activation and accordingly promotes the binding of neighboring myosin to actin. In the present study, we investigated the effects of OM on the steady-state contractile properties in skinned porcine left ventricular (PLV) and atrial (PLA) muscles. OM increased Ca²⁺ sensitivity in a concentration-dependent manner in PLV, by left shifting the mid-point (pCa₅₀) of the force-pCa curve (ΔpCa₅₀) by ∼0.16 and ∼0.33 pCa units at 0.5 and 1.0 μM, respectively. The Ca²⁺-sensitizing effect was likewise observed in PLA, but less pronounced with ΔpCa₅₀ values of ∼0.08 and ∼0.22 pCa units at 0.5 and 1.0 μM, respectively. The Ca²⁺-sensitizing effect of OM (1.0 μM) was attenuated under enhanced thin filament cooperative activation in both PLV and PLA; this attenuation occurred directly via treatment with fast skeletal troponin (ΔpCa₅₀: ∼0.16 and ∼0.10 pCa units in PLV and PLA, respectively) and indirectly by increasing the number of strongly bound cross-bridges in the presence of 3 mM MgADP (ΔpCa₅₀: ∼0.21 and ∼0.08 pCa units in PLV and PLA, respectively). It is likely that this attenuation of the Ca²⁺-sensitizing effect of OM is due to a decrease in the number of "recruitable" cross-bridges that can potentially produce active force. When cross-bridge detachment was accelerated in the presence of 20 mM inorganic phosphate, the Ca²⁺-sensitizing effect of OM (1.0 μM) was markedly decreased in both types of preparations (ΔpCa₅₀: ∼0.09 and ∼0.03 pCa units in PLV and PLA, respectively). The present findings suggest that the positive inotropy of OM is more markedly exerted in the ventricle than in the atrium, which results from the strongly bound cross-bridge-dependent allosteric activation of thin filaments.

Keywords: Ca2+ sensitivity; contractility; myocardium; sarcomere; thin filament.